Verotoxins that enterohemorrhagic Escherichia coli O157:H7 produces are proteins belonging to the AB5 family of bacterial toxins analogous to Shiga toxin derived from dysentery bacillus, and it has been known that these toxins are incorporated into cells by recognizing and bonding a globo3 sugar moiety of globotriaosylceramide (Gb3, Galα1-4Galβ1-4G1cβ1-Cer) in vascular endothelial cells of various target organs to show a toxicity.
Such Shiga-like toxins include two types, and these toxins induce hemorrhagic colitis, severe complications as a series of consequential microvascular disorders [for example, hemolytic uremic syndrome (HUS)] and the like. A toxin expressed as STX1 has the same amino acid sequence as Shiga toxin produced by Shigella dysenteriae [Shigella dysenteriae Type I). Meanwhile, a toxin expressed as STX2 has an amino acid sequence which is identified to be homologous to that of STX1 by 50 to 60%. Although there is a slight difference in amino acid sequence, toxicities thereof show activities such as a cytotoxicity and an intestinal toxicity by inhibition of protein synthesis. STX is an AB5-type toxin comprising two types of subunits (A and B) in which one molecule of A-subunit is surrounded by five molecules of B-subunit via hydrophobic binding. It is A-subunit that plays a roll in toxicity, and B-subunit plays a roll in binding to a sugar chain receptor present on the surface of the cell. Through detailed examination by analysis of X-ray crystal structure of the toxin, it has been clarified that three binding sites of a sugar chain are present in one molecule of B-subunit. That is, since five molecules of B-subunit are present in STX2 of one molecule, it is presumed that 15 binding sites in total are presented.
That is, STX is classified in two families, STX1 and STX2. It is mainly STX2 producing bacteria that induce severe complications, and STX2 is more significant clinically. For this reason, the development of an inhibitor of STX2 is urgently required. These STXs are A-B5-type toxins, and incorporated into cells such that B-subunit is bound to Gb3 (globotriaosylceramide: Gala(1-4)-Galβ(1-4)-Galcβ1-Ceramide), a receptor on the cell membrane. A B-subunit pentamer specifically recognizes a Gb3 sugar chain moiety (globo3 sugar: Galα(1-4)-Galβ(1-4)-G1cβ1-). Accordingly, a compound in which globo3 sugar is accumulated at high density is bound to STX with high affinity, and becomes an STX inhibitor of inhibiting its function.
Since the subunit structure of the toxin and its function have been clarified, a method for selectively inhibiting the binding of B-subunit having a function of binding to the sugar chain receptor on the cell surface has attracted much interest, and studies thereof have been made from various aspects.
The inventors of this application have also conducted construction of an artificial sugar chain cluster which effectively binds the sugar chain to the sugar chain binding site of the toxin to inhibit the adhesion of the toxin to the host cell. They have so far proposed a dendrimer compound group having carbosilane as a sugar chain-supporting structure or water-soluble polymer compounds (Patent Documents 1 and 2, and non-Patent Document 1).
Examples thereof include SUPER TWIG (1)6 represented by the following formula, and the like. This is the first compound whose effectiveness has been verified in an O157:H7 infection experiment.

The past development of STX inhibitors including SUPER TWIG has been conducted on the basis of the concept of how the globo3 sugar as an STX-binding unit is accumulated for exhibiting an inhibitory activity in vivo. However, an affinity (Kd) for STX with the globo3 sugar alone is 10−3 M which is not necessarily high, and its chemical synthesis is quite difficult. This is a great barrier to clinical application. Accordingly, for the development of clinically applicable therapeutic agents, the development of a new STX-binding unit which is easier to synthesize than the globo3 sugar and excellent in bindability to STX is required.
Further, it is presumed that the foregoing problem is not only peculiar to the verotoxin but also common to, other than the verotoxin STX, cholera toxin (A-B5 type) receptor: GM1, enterotoxigenic Escherichia coli heat-labile diarrhea causal toxin LT (A-B5 type) receptor: GM1, pertussis toxin (A-B5 type) receptor, Bacillus anthracis toxin (heptamer type) receptor: protein having VWA domain (anthrax toxin receptor) in which a receptor binding portion is considered to have a subunit structure, and the like.
Under these circumstances, the inventors of this application have conducted investigations to construct a substance formulated as a receptor of these toxins.
Patent Document 1: WO 02/02588
Patent Document 2: Japanese Patent Application No. 2004-108483
Non-Patent Document 1: Proc. Natl. Acad. Sci. USA 2002; 99; 7669-74